Carboplatin vs Olaparib for Prostate Cancer (COBRA Trial)
Recruiting in Palo Alto (17 mi)
+18 other locations
Age: 18+
Sex: Male
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: VA Office of Research and Development
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This is an unblinded, randomized clinical study comparing the efficacy of DNA damaging chemotherapy using carboplatin, to standard of care therapy for patients who have metastatic castrate resistant prostate cancer. This trial will use olaparib or carboplatin as initial therapy with crossover to the alternate or second-line drug after first progression for patients with tumors containing BARD1, BRCA1, BRCA2, BRIP1, CHEK1, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L inactivating mutations.
Participants are randomized (1:1) and receive either carboplatin (AUC 5, IV) every 21 days, first or olaparib taken orally (300 mg), twice daily in 28 day cycles, until intolerance, complete response, or progression by Prostate Cancer Working Group 3 (PCWG3) criteria.
Participants then crossover from the first-line therapy to the second-line therapy with the opposite study medication and receive treatment to intolerance or progression (whichever is first). Enrolled participants will be allowed to crossover to second line therapy if they continue to meet initial eligibility criteria, and at least three weeks have elapsed since last administration of either carboplatin or olaparib. Throughout the study, safety and tolerability will be assessed. Progression will be evaluated with bone scan, CT of the abdomen/pelvis, or MRI and PSA as per PCWG3 criteria.
What data supports the idea that Carboplatin vs Olaparib for Prostate Cancer is an effective drug?
The available research shows that Olaparib, when combined with another treatment called radium-223, has shown early clinical benefits for men with a specific type of prostate cancer that has spread to the bones. In a study, 58% of patients did not see their cancer worsen for at least 6 months. This suggests that Olaparib can be an effective part of a treatment plan for prostate cancer, especially when used with radium-223. However, there is no direct comparison with Carboplatin for prostate cancer in the provided data.
23567Do I have to stop taking my current medications for the trial?
The trial protocol does not specify if you must stop all current medications. However, you must stop taking strong or moderate CYP3A inhibitors and inducers before starting olaparib. The washout period is 2 weeks for inhibitors and 3-5 weeks for inducers, depending on the specific medication.
Is the drug Carboplatin, Olaparib a promising treatment for prostate cancer?
The combination of Carboplatin and Olaparib shows promise as a treatment for prostate cancer. Olaparib, a drug that helps prevent cancer cells from repairing themselves, has shown early clinical benefits when used with other treatments. Although the studies mainly focus on other types of cancer, the combination has been safe and effective in trials, suggesting potential for prostate cancer treatment.
24567What safety data exists for Carboplatin and Olaparib in prostate cancer treatment?
The safety data for Olaparib in prostate cancer treatment includes findings from a Phase I study where Olaparib was combined with Radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. The study identified dose-limiting toxicities such as cytopenias, fatigue, and nausea, with the most common treatment-related adverse events being fatigue (92%) and anemia (58%). The recommended phase 2 dose (RP2D) of Olaparib was established at 200 mg orally twice daily with Radium-223. No specific safety data for Carboplatin in prostate cancer was provided in the research.
12367Eligibility Criteria
Men over 18 with advanced prostate cancer that's resistant to hormone therapy and has specific gene mutations (like BRCA1/2). They must have ongoing hormone treatment, measurable disease progression, normal organ/bone marrow function, no brain metastasis or other cancers being treated, and not taken certain drugs before.Inclusion Criteria
My prostate cancer is resistant to medical or surgical treatments to lower testosterone.
My scans show my bone cancer has worsened with more than 2 new spots.
I have been treated with medications like abiraterone, enzalutamide, apalutamide, or darolutamide.
I am mostly self-sufficient and can carry out daily activities.
My cancer has specific mutations (RAD51B/C/D or RAD54L) confirmed by a certified test.
I am on hormone therapy for cancer or have had surgery to remove my testicles.
I am a man older than 18.
I have been diagnosed with prostate cancer, but it's not the small-cell or high-grade neuroendocrine type.
My kidneys work well enough, based on a specific calculation.
Exclusion Criteria
I am currently undergoing treatment for another cancer.
I have been diagnosed with myelodysplastic syndrome or acute myeloid leukemia.
I have been treated with platinum, mitoxantrone, or PARP inhibitors for prostate cancer.
I do not have active hepatitis or severe liver disease.
I have had a heart attack or serious heart disease in the last 6 months.
I am not taking strong or moderate CYP3A inhibitors, or I can stop them for 2 weeks before starting olaparib.
I am not currently using, or have stopped using strong or moderate drugs that affect liver enzymes as required before starting olaparib.
I cannot swallow pills or have stomach issues affecting medication absorption.
I have brain metastases.
Participant Groups
The trial compares carboplatin chemotherapy to olaparib pills for men with a type of advanced prostate cancer. Patients are randomly chosen to start with one drug and can switch to the other if the first one stops working. The study checks how well each drug controls the cancer.
2Treatment groups
Active Control
Group I: Treatment Arm 2 - Olaparib to CarboplatinActive Control2 Interventions
Participants are prescribed olaparib which is taken orally at home, twice daily, 300 mg in 28 day cycles, as first line therapy. For second line (crossover), carboplatin is administered AUC 5 IV every 21 days thereafter.
Group II: Treatment Arm 1 - Carboplatin to OlaparibActive Control2 Interventions
Participants are administered carboplatin AUC 5 IV first, which is administered Cycle-1, Day-1, and then every 21 days as first line therapy. For second line (crossover), olaparib is prescribed and taken orally at home, twice daily, 300 mg in 28 day cycles.
Carboplatin is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Paraplatin for:
- Ovarian cancer
- Testicular cancer
- Lung cancer
- Head and neck cancer
- Brain cancer
🇪🇺 Approved in European Union as Carboplatin for:
- Ovarian cancer
- Small cell lung cancer
🇨🇦 Approved in Canada as Carboplatin for:
- Ovarian cancer
- Small cell lung cancer
- Testicular cancer
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Minneapolis VA Health Care System, Minneapolis, MNMinneapolis, MN
VA Ann Arbor Healthcare System, Ann Arbor, MIAnn Arbor, MI
Manhattan Campus of the VA NY Harbor Healthcare System, New York, NYNew York, NY
Durham VA Medical Center, Durham, NCDurham, NC
More Trial Locations
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Who is running the clinical trial?
VA Office of Research and DevelopmentLead Sponsor
References
Olaparib: first global approval. [2020]Olaparib (Lynparza™) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor being developed by AstraZeneca for the treatment of solid tumours. The primary indication that olaparib is being developed for is BRCA mutation-positive ovarian cancer. A capsule formulation of the drug has received approval for use in this setting in the EU and USA, and a tablet formulation is in global phase III trials (including in the USA, EU, Australia, Brazil, Canada, China, Israel, Japan, Russia and South Korea). In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. This article summarizes the milestones in the development of olaparib leading to this first approval for ovarian cancer.
Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. [2022]The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy.
Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. [2022]This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed.
Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer. [2019]Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination.Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1-7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1-7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum-DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum-DNA adducts.Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%).Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib. Clin Cancer Res; 23(6); 1397-406. ©2016 AACR.
Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. [2020]The poly(ADP-ribose) polymerase inhibitor olaparib (Lynparza™) is approved for maintenance treatment of platinum-sensitive relapsed ovarian cancer. OPINION is a single-arm, open-label, multicenter, Phase IIIb study to assess the efficacy and safety of olaparib tablet maintenance therapy in women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer without a germline BRCA1 or BRCA2 mutation. Eligible patients should have received ≥2 prior lines of platinum-based chemotherapy and be in complete or partial response following their most recent course or have no evidence of disease. Patients will receive olaparib tablets (300 mg twice daily) until disease progression, unacceptable toxicity or another discontinuation criterion. The primary end point is investigator-assessed progression-free survival; secondary end points include progression-free survival according to tumor homologous recombination deficiency status. Clinical trial registration: NCT03402841.
New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]Olaparib (Lynparza) is now approved for the adjuvant treatment of adult patients who have, or are suspected to have, the germline variation of BRCA-mutated human epidermal growth factor receptor 2-negative high-risk early breast cancer and who were previously treated with neoadjuvant or adjuvant chemotherapy.
A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE). [2023]Given that radium-223 is a radiopharmaceutical that induces DNA damage, and olaparib is a PARP inhibitor that interferes with DNA repair mechanisms, we hypothesized their synergy in metastatic castration-resistant prostate cancer (mCRPC). We sought to demonstrate the safety and efficacy of olaparib + radium-223. We conducted a multicenter phase I 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases. The primary objective was to establish the RP2D of olaparib, with secondary objectives of safety, PSA response, alkaline phosphatase response, radiographic progression-free survival (rPFS), overall survival, and efficacy by homologous recombination repair (HRR) gene status. Twelve patients were enrolled; all patients received a prior androgen receptor signaling inhibitor (ARSI; 100%) and 3 patients (25%) prior docetaxel. Dose-limiting toxicities (DLT) included cytopenias, fatigue, and nausea. No DLTs were seen in the observation period however delayed toxicities guided the RP2D. The RP2D of olaparib was 200 mg orally twice daily with radium-223. The most common treatment-related adverse events were fatigue (92%) and anemia (58%). The rPFS at 6 months was 58% (95% confidence interval, 27%-80%). Nine patients were evaluable for HRR gene status; 1 had a BRCA2 alteration (rPFS 11.8 months) and 1 had a CDK12 alteration (rPFS 3.1 months). Olaparib can be safely combined with radium-223 at the RP2D 200 mg orally twice daily with fixed dose radium-223. Early clinical benefit was observed and will be investigated in a phase II study.